Acute hypoxia impairs posterior cerebral bioenergetics and memory in man.

Hypoxia has the potential to impair cognitive function; however, it is still uncertain which cognitive domains are adversely affected. We examined the effects of acute hypoxia (∼7 h) on central executive (Go/No-Go) and non-executive (memory) tasks and the extent to which impairment was potentially related to regional cerebral blood flow and oxygen delivery (CDO2 ). Twelve male participants performed cognitive tasks following 0, 2, 4 and 6 h of passive exposure to both normoxia and hypoxia (12% O2 ), in a randomized block cross-over single-blinded design. Middle cerebral artery (MCA) and posterior cerebral artery (PCA) blood velocities and corresponding CDO2 were determined using bilateral transcranial Doppler ultrasound. In hypoxia, MCA DO2 was reduced during the Go/No-Go task (P = 0.010 vs. normoxia, main effect), and PCA DO2 was attenuated during memorization (P = 0.005 vs. normoxia) and recall components (P = 0.002 vs. normoxia) in the memory task. The accuracy of the memory task was also impaired in hypoxia (P = 0.049 vs. normoxia). In contrast, hypoxia failed to alter reaction time (P = 0.19 vs. normoxia) or accuracy (P = 0.20 vs. normoxia) during the Go/No-Go task, indicating that selective attention and response inhibition were preserved. Hypoxia did not affect cerebral blood flow or corresponding CDO2 responses to cognitive activity (P > 0.05 vs. normoxia). Collectively, these findings highlight the differential sensitivity of cognitive domains, with memory being selectively vulnerable in hypoxia. NEW FINDINGS: What is the central question of this study? We sought to examine the effects of acute hypoxia on central executive (selective attention and response inhibition) and non-executive (memory) performance and the extent to which impairments are potentially related to reductions in regional cerebral blood flow and oxygen delivery. What is the main finding and its importance? Memory was impaired in acute hypoxia, and this was accompanied by a selective reduction in posterior cerebral artery oxygen delivery. In contrast, selective attention and response inhibition remained well preserved. These findings suggest that memory is selectively vulnerable to hypoxia.

Lower systemic nitric oxide bioactivity, cerebral hypoperfusion and accelerated cognitive decline in formerly concussed retired rugby union players.

NEW FINDINGS: What is the central question of this study? What are the molecular, cerebrovascular and cognitive biomarkers of retired rugby union players with concussion history? What is the main finding and its importance? Retired rugby players compared with matched controls exhibited lower systemic nitric oxide bioavailability accompanied by lower middle cerebral artery velocity and mild cognitive impairment. Retired rugby players are more susceptible to accelerated cognitive decline. ABSTRACT: Following retirement from sport, the chronic consequences of prior-recurrent contact are evident and retired rugby union players may be especially prone to accelerated cognitive decline. The present study sought to integrate molecular, cerebrovascular and cognitive biomarkers in retired rugby players with concussion history. Twenty retired rugby players aged 64 ± 5 years with three (interquartile range (IQR), 3) concussions incurred over 22 (IQR, 6) years were compared to 21 sex-, age-, cardiorespiratory fitness- and education-matched controls with no prior concussion history. Concussion symptoms and severity were assessed using the Sport Concussion Assessment Tool. Plasma/serum nitric oxide (NO) metabolites (reductive ozone-based chemiluminescence), neuron specific enolase, glial fibrillary acidic protein and neurofilament light-chain (ELISA and single molecule array) were assessed. Middle cerebral artery blood velocity (MCAv, doppler ultrasound) and reactivity to hyper/hypocapnia ( CVR CO 2 hyper ${\mathrm{CVR}}_{{\mathrm{CO}}_{\mathrm{2}}{\mathrm{hyper}}}$ / CVR CO 2 hypo ${\mathrm{CVR}}_{{\mathrm{CO}}_{\mathrm{2}}{\mathrm{hypo}}}$ ) were assessed. Cognition was determined using the Grooved Pegboard Test and Montreal Cognitive Assessment. Players exhibited persistent neurological symptoms of concussion (U = 109(41) , P = 0.007), with increased severity compared to controls (U = 77(41) , P < 0.001). Lower total NO bioactivity (U = 135(41) , P = 0.049) and lower basal MCAv were apparent in players (F2,39  = 9.344, P = 0.004). This was accompanied by mild cognitive impairment (P = 0.020, 95% CI, -3.95 to -0.34), including impaired fine-motor coordination (U = 141(41) , P = 0.021). Retired rugby union players with history of multiple concussions may be characterised by impaired molecular, cerebral haemodynamic and cognitive function compared to non-concussed, non-contact controls.

Effects of continuous hypoxia on flow-mediated dilation in the cerebral and systemic circulation: on the regulatory significance of shear rate phenotype.

Emergent evidence suggests that cyclic intermittent hypoxia increases cerebral arterial shear rate and endothelial function, whereas continuous exposure decreases anterior cerebral oxygen (O2) delivery. To examine to what extent continuous hypoxia impacts cerebral shear rate, cerebral endothelial function, and consequent cerebral O2 delivery (CDO2), eight healthy males were randomly assigned single-blind to 7 h passive exposure to both normoxia (21% O2) and hypoxia (12% O2). Blood flow in the brachial and internal carotid arteries were determined using Duplex ultrasound and included the combined assessment of systemic and cerebral endothelium-dependent flow-mediated dilatation. Systemic (brachial artery) flow-mediated dilatation was consistently lower during hypoxia (P = 0.013 vs. normoxia), whereas cerebral flow-mediated dilation remained preserved (P = 0.927 vs. normoxia) despite a reduction in internal carotid artery antegrade shear rate (P = 0.002 vs. normoxia) and CDO2 (P < 0.001 vs. normoxia). Collectively, these findings indicate that the reduction in CDO2 appears to be independent of cerebral endothelial function and contrasts with that observed during cyclic intermittent hypoxia, highlighting the regulatory importance of (hypoxia) dose duration and flow/shear rate phenotype.

Concussion history in rugby union players is associated with depressed cerebrovascular reactivity and cognition.

Recurrent contact and concussion in rugby union remains a significant public health concern given the potential increased risk of neurodegeneration in later life. This study determined to what extent prior-recurrent contact impacts molecular-hemodynamic biomarkers underpinning cognition in current professional rugby union players with a history of concussion. Measurements were performed in 20 professional rugby union players with an average of 16 (interquartile range [IQR] 13-19) years playing history reporting 3 (IQR 1-4) concussions. They were compared to 17 sex-age-physical activity-and education-matched non-contact controls with no prior history of self-reported concussion. Venous blood was assayed directly for the ascorbate free radical (A•- electron paramagnetic resonance spectroscopy) nitric oxide metabolites (NO reductive ozone-based chemiluminescence) and select biomarkers of neurovascular unit integrity (NVU chemiluminescence/ELISA). Middle cerebral artery blood flow velocity (MCAv doppler ultrasound) was employed to determine basal perfusion and cerebrovascular reactivity (CVR) to hyper/hypocapnia ( CVR CO 2 Hyper / Hypo ). Cognition was assessed by neuropsychometric testing. Elevated systemic oxidative-nitrosative stress was confirmed in the players through increased A•- (p < 0.001) and suppression of NO bioavailability (p < 0.001). This was accompanied by a lower CVR range ( CVR CO 2 Range ; p = 0.045) elevation in neurofilament light-chain (p = 0.010) and frontotemporal impairments in immediate-memory (p = 0.001) delayed-recall (p = 0.048) and fine-motor coordination (p < 0.001). Accelerated cognitive decline subsequent to prior-recurrent contact and concussion history is associated with a free radical-mediated suppression of CVR and neuronal injury providing important mechanistic insight that may help better inform clinical management.

Contact events in rugby union and the link to reduced cognition: evidence for impaired redox-regulation of cerebrovascular function.

NEW FINDINGS: What is the central question of this study? How does recurrent contact incurred across a season of professional rugby union impact molecular, cerebrovascular and cognitive function? What is the main findings and its importance? A single season of professional rugby union increases systemic oxidative-nitrosative stress (OXNOS) confirmed by a free radical-mediated suppression in nitric oxide bioavailability. Forwards encountered a higher frequency of contact events compared to backs, exhibiting elevated OXNOS and lower cerebrovascular function and cognition. Collectively, these findings provide mechanistic insight into the possible cause of reduced cognition in rugby union subsequent to impairment in the redox regulation of cerebrovascular function. ABSTRACT: Contact events in rugby union remain a public health concern. We determined the molecular, cerebrovascular and cognitive consequences of contact events during a season of professional rugby. Twenty-one male players aged 25 (mean) ± 4 (SD) years were recruited from a professional rugby team comprising forwards (n = 13) and backs (n = 8). Data were collected across the season. Pre- and post-season, venous blood was assayed for the ascorbate free radical (A•- , electron paramagnetic resonance spectroscopy) and nitric oxide (NO, reductive ozone-based chemiluminescence) to quantify oxidative-nitrosative stress (OXNOS). Middle cerebral artery velocity (MCAv, Doppler ultrasound) was measured to assess cerebrovascular reactivity (CVR), and cognition was assessed using the Montreal Cognitive Assessment (MoCA). Notational analysis determined contact events over the season. Forwards incurred more collisions (Mean difference [MD ] 7.49; 95% CI, 2.58-12.40; P = 0.005), tackles (MD 3.49; 95% CI, 0.42-6.56; P = 0.028) and jackals (MD 2.21; 95% CI, 0.18-4.24; P = 0.034). Forwards suffered five concussions while backs suffered one concussion. An increase in systemic OXNOS, confirmed by elevated A•- (F2,19  = 10.589, P = 0.004) and corresponding suppression of NO bioavailability (F2,19  = 11.492, P = 0.003) was apparent in forwards and backs across the season. This was accompanied by a reduction in cerebral oxygen delivery ( cDO2 , F2,19  = 9.440, P = 0.006) and cognition (F2,19  = 4.813, P = 0.041). Forwards exhibited a greater decline in the cerebrovascular reactivity range to changes in PETCO2 ( CVRCO2RANG compared to backs (MD 1.378; 95% CI, 0.74-2.02; P < 0.001).

Integrated respiratory chemoreflex-mediated regulation of cerebral blood flow in hypoxia: Implications for oxygen delivery and acute mountain sickness.

NEW FINDINGS: What is the central question of this study? To what extent do hypoxia-induced changes in the peripheral and central respiratory chemoreflex modulate anterior and posterior cerebral oxygen delivery, with corresponding implications for susceptibility to acute mountain sickness? What is the main finding and its importance? We provide evidence for site-specific regulation of cerebral blood flow in hypoxia that preserves oxygen delivery in the posterior but not the anterior cerebral circulation, with minimal contribution from the central respiratory chemoreflex. External carotid artery vasodilatation might prove to be an alternative haemodynamic risk factor that predisposes to acute mountain sickness. ABSTRACT: The aim of the present study was to determine the extent to which hypoxia-induced changes in the peripheral and central respiratory chemoreflex modulate anterior and posterior cerebral blood flow (CBF) and oxygen delivery (CDO2 ), with corresponding implications for the pathophysiology of the neurological syndrome, acute mountain sickness (AMS). Eight healthy men were randomly assigned single blind to 7 h of passive exposure to both normoxia (21% O2 ) and hypoxia (12% O2 ). The peripheral and central respiratory chemoreflex, internal carotid artery, external carotid artery (ECA) and vertebral artery blood flow (duplex ultrasound) and AMS scores (questionnaires) were measured throughout. A reduction in internal carotid artery CDO2 was observed during hypoxia despite a compensatory elevation in perfusion. In contrast, vertebral artery and ECA CDO2 were preserved, and the former was attributable to a more marked increase in perfusion. Hypoxia was associated with progressive activation of the peripheral respiratory chemoreflex (P < 0.001), whereas the central respiratory chemoreflex remained unchanged (P > 0.05). Symptom severity in participants who developed clinical AMS was positively related to ECA blood flow (Lake Louise score, r = 0.546-0.709, P = 0.004-0.043; Environmental Symptoms Questionnaires-Cerebral symptoms score, r = 0.587-0.771, P = 0.001-0.027, n = 4). Collectively, these findings highlight the site-specific regulation of CBF in hypoxia that maintains CDO2 selectively in the posterior but not the anterior cerebral circulation, with minimal contribution from the central respiratory chemoreflex. Furthermore, ECA vasodilatation might represent a hitherto unexplored haemodynamic risk factor implicated in the pathophysiology of AMS.

HIITing the brain with exercise: mechanisms, consequences and practical recommendations.

The increasing number of older adults has seen a corresponding growth in those affected by neurovascular diseases, including stroke and dementia. Since cures are currently unavailable, major efforts in improving brain health need to focus on prevention, with emphasis on modifiable risk factors such as promoting physical activity. Moderate-intensity continuous training (MICT) paradigms have been shown to confer vascular benefits translating into improved musculoskeletal, cardiopulmonary and cerebrovascular function. However, the time commitment associated with MICT is a potential barrier to participation, and high-intensity interval training (HIIT) has since emerged as a more time-efficient mode of exercise that can promote similar if not indeed superior improvements in cardiorespiratory fitness for a given training volume and further promote vascular adaptation. However, randomised controlled trials (RCTs) investigating the impact of HIIT on the brain are surprisingly limited. The present review outlines how the HIIT paradigm has evolved from a historical perspective and describes the established physiological changes including its mechanistic bases. Given the dearth of RCTs, the vascular benefits of MICT are discussed with a focus on the translational neuroprotective benefits including their mechanistic bases that could be further potentiated through HIIT. Safety implications are highlighted and components of an optimal HIIT intervention are discussed including practical recommendations. Finally, statistical effect sizes have been calculated to allow prospective research to be appropriately powered and optimise the potential for detecting treatment effects. Future RCTs that focus on the potential clinical benefits of HIIT are encouraged given the prevalence of cognitive decline in an ever-ageing population.

Long-term Exercise Confers Equivalent Neuroprotection in Females Despite Lower Cardiorespiratory Fitness.

Females are more prone to cognitive decline, stroke and neurodegenerative disease, possibly due to more marked reductions in cerebral blood flow and cerebrovascular reactivity to CO2 (CVRCO2HYPER) in later life. To what extent regular exercise confers selective neuroprotection in females remains unestablished. To examine this, 73 adults were prospectively assigned to 1 of 4 groups based on sex (male, ♂ vs. female, ♀) and physical activity status (trained, ≥150 min of moderate-vigorous intensity aerobic exercise/week; n = 18♂ vs. 18♀ vs. untrained, no formal exercise; n = 18♂ vs. 19♀). Middle cerebral artery velocity (MCAv, transcranial Doppler ultrasound), mean arterial pressure (MAP, finger photoplethysmography) and end-tidal CO2 (capnography) were assessed at rest during normocapnea and hypercapnea (5% CO2) enabling CVRCO2HYPER to be assessed. Cerebrovascular resistance/conductance indices (CVRi/CVCi) were calculated as MAP/MCAv and MCAv/MAP. Maximal oxygen uptake (VO2MAX) was determined during incremental semi-recumbent cycling ergometry to volitional exhaustion. Despite having a lower VO2MAX, females were characterized by selective elevations in MCAv, CVRCO2HYPER and lower CVRi (P < 0.05), but the training responses were similar across sexes. Linear relationships were observed between VO2MAX and CVRCO2HYPER (pooled untrained and trained data; ♂ r = 0.70, ♀ r = 0.51; both P < 0.05) with a consistent elevation in the latter equivalent to ∼1.50%.mmHg-1 compared to males across the spectrum of cardiorespiratory fitness. These findings indicate that despite having comparatively lower levels of cardiorespiratory fitness, the neuroprotective benefits of regular exercise translate into females and may help combat cerebrovascular disease in later life.